New memory manager: DNA silencer also controls memory formation.

A chemical process that switches genes off during embryonic development plays a surprising role in memory formation in adult rats, new research shows. It's the first time that scientists have seen this switching mechanism regulate normal adult cells.

The discovery adds a new layer to the control of gene activity in nerve cells, and it raises the possibility that this mechanism, called methylation, influences gene activity in other cell types as well. "This may be a more routinely used mechanism for triggering cell function," says lead researcher J. David Sweatt of the University of Alabama at Birmingham.

A developing embryo's cells become heart, liver, or another cell type by shutting down DNA that doesn't relate to the cells' eventual functions. Small molecules called methyl groups attach to a region of DNA, causing it to roll up into a tight bundle that can't be transcribed into proteins. This leaves operable only genes that are relevant to the cell's specific function.

Scientists had generally assumed that once the cells became specialized, methylation had finished its job. Aside from remethylating new copies of DNA during cell division, active methylation in adult cells is normally a sign of diseases such as schizophrenia or cancer.

Sweatt and his colleagues taught rats to fear a certain environment by giving them mild electric shocks. When placed in the same environment a day later, the rats normally froze in apparent fear, demonstrating that they had acquired long-term memories.

The researchers found that as the rats formed these memories, they showed increased activity of a family of enzymes that perform methylation. When the scientists blocked the activity of those enzymes, the rats didn't freeze when returned to an environment where they had received shocks.

Tests showed that the targets of methylation were two genes that affect memory formation: reelin and PP1. By altering the activity of those genes, methylation may be controlling the formation of new long-term memories, the group reports in the March 15 Neuron.

"I think what they're seeing is quite provocative and intriguing" comments Lisa Monteggia of the University of Texas Southwestern Medical Center at Dallas. "It certainly goes against the dogma that methylation doesn't change in the adult nervous system."

Although the experiments dealt with relatively simple stimulus-response memory in rats, "there's good reason to believe that similar mechanisms will be involved in higher forms of memory formation in humans," Sweatt says.

While the research explains how methylation affects memory formation, it remains unclear how external conditions--in this case, electric shocks--trigger the methylation. Furthermore, the process must require the later removal of methyl groups, and scientists know of no enzymes that can do this. Nor do they know of molecular mechanisms that could be doing this methylation and demethylation so quickly, Sweatt says.